Effectiveness of OHSS Prevention Strategies: Lessons from German IVF Registry

1. Prevention of ovarian hyperstimulation syndrome in OHSS patients Georg Griesinger University Clinic of Schleswig-Holstein, Campus Luebeck Dept. of Obstetrics and Gynecology VVOG Post-Universitaire Studiedag Zemst, 13 Nov 2008

2. What is the OHSS incidence in your center?

3. German IVF registry, 2006

4. Number of OHSS cases per year in Germany? • 0,41 (incidence DIR) x ~40.000 IVF cycles with ovarian stimulation per year = 164 OHSS cases

5. = 1.080 OHSS III cases per year in Germany Hum Reprod. 2006 Dec;21(12):3235-40

6. OHSS III° incidence: 2,1% 95% CI: 1.6 – 2.8 Fertility and Sterility Vol. 85, No. 1, 2006

7. OHSS [MeSH] AND fatality [MeSH] • death of a 31-year-old woman …who developed a fatal adult respiratory distress syndromeFineschi et al., 2006 • autopsy case of severe OHSS …..28-year-old Japanese female…… who died of rapid respiratory insufficiencySemba et al., 2000 • 21 yearoldwoman ……cerebralinfarction….complete persistent hemiplegia Hwang et al., 1998 • ........................

10. primaryprevention: intendedtodecreasetheoverallrisk in thegeneralpopulation • secondaryprevention: detectionofpatients atriskandpreventivemeasureonly in thosepatients • tertiaryprevention: prophylaxisoffurtherdamage in patientswith a disease

11. Can we reliably predict OHSS?

12. Long GnRH-agonist protocol De Angelo et al., 2004 E2 = 3,354 pg/ml Sens + Spec = 85% GnRH-antagonist protocol Papanicolaou et al., 2006 18 follicles >10 mm or E2 > 5,000 pg/l Sens = 83% Spec = 84% 5/53 CASES OF SEVERE OHSS STILL MISSED WITH THESE CRITERIA

13. Noreliabletesttoidentify all OHSS riskpatients • developovarianstimulationroutinesthatareassociatedwith a per se decreasedriskof OHSS (primaryprevention) • developmeasuresof OHSS preventionfor individual riskpatients, whicharesafeandefficacious, andcanthereforebeliberallyutilized (secondaryprevention) • developbettertreatmentregimenforpatientswithonsetof OHSS toavoidfurthercomplications (tertiaryprevention)

14. OHSS Prevention

15. Ovarian stimulation • OHSS incidence reduction • Natural cycle IVF √ • In vitro Maturation √ • Cycle cancellation √ efficacy ? ? ---

16. Number-needed-to-treat-to-harm with a GnRH-agonist long protocol for OHSS III Kolibianakis et al., Hum Reprod Update 2006 EXPECTED OHSS III° INCIDENCE: 3.5% RR = 0.47, 95% CI 0.27–0.82, P = 0.01 NNT TO HARM = 53 (39 - 159) 3,46%

17. GnRH-antagonist vs GnRH-agonist long OHSS III Crude incidence of OHSS = 1.5%

18. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial Incidence of OHSS = 1.4% Heijnen et al.,Lancet 2007; 369: 743–49

19. Coasting OHSS II-III in 3-10% Delvigne & Rozenberg, HRupdate, 2002

20. GnRH -antagonists

21. Novel concepts in Coasting E2 < 3000 pg/ml ? 4 follicles ≥ 16mm? Hyper response? hCG FSH FSH GnRH-agonist daily GnRH-antagonist daily n= 85, coasting ~ 1.5 days Ongoing pregnancy rate: ~ 60 % Severe OHSS: 1.5 - 7.5 % Gustofson et al., Hum Reprod 2006 Gustofson et al., Fertil Steril 2006

22. Novel concepts in Coasting RCT: 192 patients Aboulghar et al., RBMonline 2007

23. Coasting in Antagonist protocols Bahceci et al., 2006; Farhi et al., 2008

24. Ovarian stimulation

25. OHSS Prevention

26. The final solutionto OHSS prevention….. • AbolishhCGas a triggeringagent!?

27. GnRH-agonisttrigger Gonen et al., 1990

28. Luteal phase after agonist trigger? • Progesteroneserumvalueswith • NO • lutealphasesupplementation Day ofadministrationofGnRH-a orhCG Beckers et al., 2003

29. Drastic luteolysis… • Will itprevent OHSS? Kol S, Fertil Steril 2004

30. Does GnRH-agonist triggering prevent OHSS? RCT

31. OHSS I-II: RR with 95% confidence intervals (heterogeneity p = 0.57) OHSS III: RR with 95% confidenceintervals (heterogeneity p = 0.90) Update of: Griesinger et al., Hum Reprod update 2005

32. Evidence from observational, uncontrolled trials16 publicationstotal n= 1,091 OHSS risk patients  a single case reported: late-onset OHSS in a pregnant woman Update of: Griesinger et al., RBMonline 2006

33. No difference between • 0.2 triptorelin or 0.5 mg buserelin and hCG • no. of oocytes • no. of MII oocytes • fertilisationrate • embryo Score • BUT: • ongoing PR drastically reduced Human Reproduction Update, 2006

34. Griesinger et al., Hum Reprod 2007

35. Cryopreservation slow cooling vitrification 2 sec. - 50.000°C/min

36. Update of Griesinger et al., Hum Reprod 2007

37. Update of Griesinger et al., Hum Reprod 2007

38. Mean number of ETs: 2.1 Mean number of embryos transferred 2.1 Mean time-to-conception 21 weeks Cumulative incidence positive hCG test leading to live birth

39. Reduced hCG dose? • RCT, n= 80 PCOS • GnRH-antagonist protocol Kolibianakis et al., 2007

40. low dose hCG & OHSS? • Retrospective study, n=94 cycles • > 2,500 - 4,000 pg/mL  5000 IU • >4000  3300 IU Schmidt et al., 2007

41. Half dose/low dose hCG & OHSS? • Observational pilot study • 2.500 vs. 5.000 IU hCG • n = 21 OHSS high-risk patients • 62% ongoing pregnancy rate • 0 % OHSS Nargund et al., 2007 Craft, 2007

42. OHSS Prevention

44. Clinical pregnancy rate per ET Griesinger, GebFra 2006

45. Novel concept: Luteal phase antagonist hCG 3 dayslater…. early OHSS GnRH-antagonist daily GnRH-antagonist daily FSH Report on 3 cases with early-onset OHSS Lainas et al., RBMonline 2007

46. Novel concepts: cabergoline VEGF

47. Novel concepts in treatment: Cabergolin Background: Vascular fluid leakage VEGF VEGF R1 Cabergoline Dopamine R agonist Alvarez et al, JCEM 2007

48. RCT: placebo-controlled Intervention: Cab 0.5 mg, day hCG  hCG+8 Patients: oocyte donors Inclusion: > 20 oocytes retrieved Alvarez et al, JCEM 2007 & Alvarez, Hum Reprod 2007